Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains
Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains
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DOI：
10.1113/jphysiol.2014.285890
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发表时间：
2015-02-15
影响因子：
5.5
通讯作者：
Cragg, Stephanie J.
中科院分区：
文献类型：
--
作者：
Brimblecombe, Katherine R.;Gracie, Caitlin J.;Cragg, Stephanie J.
电压门控钙通道（VGCC）催化纹状体多巴胺的传输是至关重要的多巴胺功能，并可能引发帕金森氏变性的神经元亚群。然而，VGCCs的中纹状体轴突上运作是不完全定义的，以前的研究包括通道纹状体胆碱能中间神经元，强烈影响多巴胺的传输。我们定义了多种类型的轴突VGCC的操作，扩展到经典的突触前N/P/Q通道，包括T型和L型。我们揭示了小鼠轴突类型之间VGCC功能的差异，在人类中是脆弱的与抗帕金森病。我们第一次表明，这是由不同的敏感性多巴胺传输到细胞外Ca 2+和不同的时空细胞内Ca 2+微域。这些数据定义了钙离子和VGCC如何在健康大脑中管理多巴胺传输的关键原则，并揭示了可能导致疾病脆弱性的神经元类型之间的差异。AbstractThe axonal voltage-gated Ca 2 + channels（VGCC）that catalyze dopamine（DA）transmission is incompletely defined.然而，他们是至关重要的DA功能，并可能总理亚群的DA神经元帕金森氏变性。以前的研究VGCC将包括纹状体胆碱能中间神经元，这强烈影响DA的传输。我们确定哪些VGCC的DA轴突管理DA传输，我们确定其动态特性，并揭示了尾壳核（CPu）和核神经元（NAc）之间的差异的基础。我们检测到DA释放诱发电烟碱受体阻断或光遗传学的光激活通道视紫红质表达DA轴突在小鼠纹状体切片。亚型特异性VGCC阻断剂表明，N-，Q-，T-和L-VGCC控制CPu中的DA释放，但在NAc中，T和L-通道相对沉默。最主要的通道的作用是负频率依赖性的，由于低通滤波DA释放的Ca 2+依赖的初始释放概率和短期可塑性之间的关系。Ca 2+浓度-反应曲线显示，CPu和NAc之间的差异是由于更大的潜在的Ca 2+敏感性的DA传输从CPu轴突。NAc中沉默的L-和T-通道的功能可以通过升高细胞外[Ca ~（2+）]来揭示。此外，我们确定了一个更大的耦合BAPTA敏感，快速Ca 2+瞬变和DA传输在CPu轴突，和内源性快速缓冲的Ca 2+在NAc的证据。这些数据表明，一系列的VGCC动态DA轴突上运行，这取决于当地的驱动力。此外，他们揭示了轴突亚群之间的Ca 2+处理的显着差异，表现出不同的脆弱性帕金森病变性。
The voltage-gated Ca2+ channels (VGCCs) that catalyse striatal dopamine transmission are critical to dopamine function and might prime subpopulations of neurons for parkinsonian degeneration. However, the VGCCs that operate on mesostriatal axons are incompletely defined; previous studies encompassed channels on striatal cholinergic interneurons that strongly influence dopamine transmission. We define that multiple types of axonal VGCCs operate that extend beyond classic presynaptic N/P/Q channels to include T- and L-types. We reveal differences in VGCC function between mouse axon types that in humans are vulnerable versus resistant to Parkinson's disease. We show for the first time that this is underpinned by different sensitivity of dopamine transmission to extracellular Ca2+ and by different spatiotemporal intracellular Ca2+ microdomains. These data define key principles of how Ca2+ and VGCCs govern dopamine transmission in the healthy brain and reveal differences between neuron types that might contribute to vulnerability in disease.AbstractThe axonal voltage-gated Ca2+ channels (VGCCs) that catalyse dopamine (DA) transmission are incompletely defined. Yet, they are critical to DA function and might prime subpopulations of DA neurons for parkinsonian degeneration. Previous studies of VGCCs will have encompassed those on striatal cholinergic interneurons, which strongly influence DA transmission. We identify which VGCCs on DA axons govern DA transmission, we determine their dynamic properties and reveal an underlying basis for differences between the caudate putamen (CPu) and nucleus accumbens (NAc). We detected DA release evoked electrically during nicotinic receptor blockade or optogenetically by light activation of channel rhodopsin-expressing DA axons in mouse striatal slices. Subtype-specific VGCC blockers indicated that N-, Q-, T- and L-VGCCs govern DA release in CPu, but in NAc, T and L-channels are relatively silent. The roles of the most dominant channels were inversely frequency-dependent, due to low-pass filtering of DA release by Ca2+-dependent relationships between initial release probability and short-term plasticity. Ca2+ concentration-response curves revealed that differences between CPu and NAc were due to greater underlying Ca2+ sensitivity of DA transmission from CPu axons. Functions for silent' L- and T-channels in NAc could be unmasked by elevating extracellular [Ca2+]. Furthermore, we identified a greater coupling between BAPTA-sensitive, fast Ca2+ transients and DA transmission in CPu axons, and evidence for endogenous fast buffering of Ca2+ in NAc. These data reveal that a range of VGCCs operate dynamically on DA axons, depending on local driving forces. Furthermore, they reveal dramatic differences in Ca2+ handling between axonal subpopulations that show different vulnerability to parkinsonian degeneration.